1. Field of the Invention
The present invention is directed to new solid dose forms of nanoparticulate naproxen having improved dissolution rates, methods of making such formulations, and methods of using such formulations.
2. Description of the Related Art
Naproxen, also known as (S)-6-methoxy-.alpha.-methyl-2-napthaleneacetic acid and d-2-(6-methoxy-2-naphthyl)propionic acid, is a well-known anti-inflammatory, analgesic, and antipyretic agent. It has been approved in many countries around the world for almost two decades and has a very safe risk-benefit profile. It is sold under the trade names ALEVE.RTM. (distributed by Bayer), ANAPROX.RTM., NAPROSYN.RTM., and SYNFLEX.RTM. (all manufactured by Roche Laboratories, Inc.). See The Merck Index, 11.sup.th Edition, pp. 6330 (Merck & Co., Rahway, N.J., 1989).
Naproxen, which is highly water insoluble, i.e., less than 10 mg/ml, has the following chemical structure: ##STR1##
The degree and timing in which a drug becomes available to the target tissue after administration is determined by many factors, including the dosage form and various properties, e.g. dissolution rate, of the drug. Poor onset of action is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water, such as naproxen. Poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation, and tend to have an extended period following administration prior to onset of action.
The dissolution rate of a particulate drug can increase with increasing surface area, i.e., decreasing particle size. An increased dissolution rate can lead to a faster onset of action. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. Methods of making nanoparticulate compositions are described in U.S. Pat. No. 5,145,684 for "Surface Modified Drug Nanoparticles," hereby specifically incorporated by reference.
Another method for increasing the rate of disintegration of a solid-dose formulation of a drug includes the use of effervescent tablets. In addition to the drug substance, effervescent tablets contain sodium bicarbonate and an organic acid, such as tartaric or citric. In the presence of water, these additives react liberating carbon dioxide which acts as a disintegrator and produces effervescence. Gennaro, ed., Remington's, 14.sup.th Edition, page 1634 (Mack Publishing Co., 1990). Exemplary compounds that have been formulated as effervescent tablets include aspirin and naproxen (Ross-Lee et al., "Plasma Levels of Aspirin Following Effervescent and Enteric Coated Tablets, and Their Effect on Platelet Function, Eur. J. Clin. Pharmacol., 23:545-51 (1982); Kristensen et al., "Relief of Pain and Trismus in Patients Treated with Naproxen or Acetylsalicylic Acid After Tonsillectomy," J. Laryngol. Otol., 102:39-42 (1988)); levodopa (Nishimura et al., "Dosage Form Design for Improvement of Bioavailability of Levodopa VI: Formulation of Effervescent Enteric-coated Tablets," J. Pharm. Sci., 73:942-6 (1984)), and amoxicillin (Hespe et al., "Bioavailability of New Formulations of Amoxicillin in Relation to its Absorption Kinetics," Arzneimittelforschungf, 37:372-5 (March, 1987)).
Naproxen is a non-steroidal anti-inflammatory drug (NSAID) often used to relieve the inflammation, swelling, stiffness, and joint pain associated with rheumatoid arthritis, osteoarthritis (the most common form of arthritis), juvenile arthritis, ankylosing spondylitis (spinal arthritis), tendinitis, bursitis, and acute gout. In addition, it is used to treat pain associated with menstrual periods, migraine headaches, and other types of mild to moderate pain.
Naproxen is a more potent pain reliever than aspirin, especially for menstrual cramps, toothaches, minor arthritis, and injuries accompanied by inflammation, such as tendinitis. The naproxen sodium salt is specifically indicated in the treatment of various types of acute and very high intensity pain because it induces a rapid and sustained remission. In addition, it is possible to obtain a good analgesic effect with few administrations, due to naproxen's particular pharmacokinetics. Tablet formulations of naproxen were approved for OTC ("over the counter" as compared to prescription) marketing by the U.S. Food and Drug Administration in 1994.
Naproxen acts by suppressing the production of prostaglandins, which are hormone-like substances that act on local tissues to produce pain and inflammation. Its pharmaceutical forms of delivery include tablets, capsules, and liquids. Delivery characteristics and forms are disclosed in, for example, U.S. Pat. Nos. 3,904,682; 4,009,197; 4,780,320; 4,888,178; 4,919,939; 4,940,588; 4,952,402; 5,200,193; 5,354,556; 5,462,747; and 5,480,650, all of which are specifically incorporated by reference. The synthesis of naproxen is described in, for example, U.S. Pat. Nos. 3,904,682 and 4,009,197, both of which are specifically incorporated by reference.
There is currently a need for naproxen formulations having a faster rate of dissolution following administration and which, therefore, likely have a faster onset of action. In addition, there is a need in the art for methods of making and methods of using such naproxen formulations. The present invention satisfies these needs.